Development of a Dynamic Model for Personalized Risk Assessment in Large B-Cell Lymphoma

Abstract Background: Outcomes for patients with diffuse large B-cell lymphoma (DLBCL) remain heterogeneous. Several clinical and molecular risk factors have been described, both at time of diagnosis (i.e., International Prognostic Index and cell of origin) and during therapy (i.e., interim PET scans). However, these risk factors fail to consistently identify individuals destined for treatment failure. We recently described circulating tumor DNA (ctDNA) as a novel biomarker in DLBCL, demonstrating pretreatment ctDNA levels are prognostic of outcomes (Scherer F, Sci Transl Med 2016). A major advantage of ctDNA assessment is the ability to collect serial assessments over time. However, the best approach for integrating multiple ctDNA measurements with established prognostic factors remains unknown. Using the dynamics of ctDNA, we developed a method to quantify personalized disease risk as it changes during therapy. Methods: We profiled 468 samples from 125 subjects collected during their first three cycles of immunochemotherapy using cancer personalized profiling by deep sequencing (CAPP-Seq). Early ctDNA dynamics were correlated with outcomes in a training cohort to define a response threshold that was tested in a validation cohort. Finally, we integrated ctDNA and clinical factors to dynamically assess disease risk over time in a continuous model. Results: Prior to therapy, ctDNA was detectable in 98% of subjects. Pretreatment levels of ctDNA were prognostic of event-free survival in patients receiving either frontline anthracycline-based (n=92) or salvage regimens (n=33) (EFS: HR 2.7, 95% CI 1.5-4.7, P=0.0005), confirming prior results. In the training cohort, ctDNA levels changed rapidly, with a 2-log or 100-fold decrease after one cycle (early molecular response, EMR) stratifying outcomes (Fig 1A). In the validation cohort, patients achieving EMR had superior outcomes at 24-months to those who did not (Fig 1B) (EFS: HR 24, 95% CI 6.6-89, P<0.0001). These results remained significant in subgroups of patients receiving either frontline or salvage therapy. Circulating tumor DNA levels continued to decline during cycle 2, such that a distinct threshold after two cycles could also be trained. After two cycles, a 2.5-log decrease (major molecular response, MMR) also stratified patients for EFS (HR: 8.6, 95% CI 2.2-33, P=0.002). Next, we integrated serial ctDNA measurements with established risk-factors to develop a model to predict an individual's disease risk. This model - the Continuous Individualized Risk Index (CIRI) - provides a personalized estimate of disease risk over time. As more information becomes available during a patient's course of disease, CIRI updates the disease risk, integrating the new information (Fig 1C). In patients receiving frontline therapy, CIRI outperformed the IPI for identification of 24-month EFS and OS (Fig 1D-E) (EFS24: AUC 0.64 vs 0.79; net reclassification improvement 0.47, P=0.02; OS: AUC 0.56 vs 0.84; net reclassification improvement 0.74, P=0.004). Conclusions: Baseline and interim ctDNA measurements have prognostic significance in aggressive lymphomas. Integration of serial ctDNA measurements through a continuous, dynamic risk model can identify personalized outcome probabilities, yielding superior risk estimates. Dynamic risk assessment is potentially widely applicable and could guide future personalized therapeutic approaches. Figure 1: A) A spider-plot depicts the dynamics of ctDNA during the first two cycles of therapy in 14 subjects. B) A Kaplan-Meier estimate depicts EFS for patients achieving or not achieving EMR. C) A schema for CIRI is shown. When a patient is diagnosed with DLBCL, the IPI is calculated, giving an initial estimate of risk. Additional pretreatment risk factors (i.e., cell of origin and pretreatment ctDNA) can be added, thereby updating the estimate of risk. As a patient undergoes therapy, further predictors of risk are obtained, such as ctDNA at cycle 2 and cycle 3, and interim imaging. These predictors can be used to update the patient's estimated risk. Below is a CIRI risk model for two exemplar patients with the same initial pretreatment risk factors. Patient P214 (red) died of disease at day 210, while patient P224 (blue) is in a continued complete response. D) AUC for prediction of EFS and OS by IPI, EMR, interim PET scans, and CIRI. E) A Kaplan-Meier estimate demonstrates risk stratification of EFS by CIRI. Disclosures Advani: Sutro: Consultancy; Cell Medica: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Research Funding; Nanostring: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Juno Therapeutics: Consultancy; FortySeven: Research Funding; Gilead: Consultancy; Spectrum: Consultancy; Pharmacyclics: Research Funding; Agensys: Research Funding; Regeneron: Research Funding; Millennium: Research Funding; Infinity: Research Funding; Merck: Research Funding; Kura: Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Research Funding; Genentech: Research Funding. Newman: Roche: Consultancy. Westin: Celgene: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Gaidano: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Diehn: Varian Medical Systems: Research Funding; Roche: Consultancy; Novartis: Consultancy; Quanticel Pharmaceuticals: Consultancy. Alizadeh: Genentech: Consultancy; Celgene: Consultancy; CiberMed: Consultancy; Roche: Consultancy; Gilead: Consultancy.

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Validation of the International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET) in Patients with Pre-Fibrotic Primary Myelofibrosis

Blood ◽

10.1182/blood-2019-124302 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1657-1657

Author(s):

Paola Guglielmelli ◽

Alessandra Carobbio ◽

Elisa Rumi ◽

Valerio De Stefano ◽

Lara Mannelli ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Incidence Rate ◽

Research Funding ◽

Risk Model ◽

Univariate Analysis ◽

Thrombotic Event ◽

Advisory Committees ◽

Thrombotic Risk

Introduction. Prefibrotic myelofibrosis (pre-PMF) is a unique entity in the 2016 WHO classification of myeloproliferative neoplasms with distinct clinical phenotype and outcome [Guglielmelli P, Blood 2017]. Compared to essential thrombocythemia (ET), pre-PMF is characterized by more pronounced disease manifestations, adverse mutation profile and worse outcome. Previous studies [Rumi E, Oncotarget 2017] showed that patients (pts) with pre-PMF present a risk of vascular events similar to ET. However, no studies performed a comprehensive assessment of risk factors for thrombosis in pre-PMF. The current study aimed to identify risk factors for thrombosis and bleeding in a large series of pre-PMF pts and explore the effectiveness of contemporary prognostic models developed specifically for ET. Patients and Methods. The study included 382 pre-PMF pts, diagnosed by 2016 WHO criteria, referred by 4 Italian Centers. Previously published methods were used to genotype JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2; a high molecular risk (HMR) category was defined according to Vannucchi A, [Leukemia 2013]. Thrombosis‐free survival (TFS) was determined from diagnosis to the first thrombotic event. Pts were grouped according to the conventional risk stratification system [Barbui T, JCO 2011], IPSET‐thrombosis [Barbui T, Blood 2012] and revised IPSET‐thrombosis [Barbui T, BCJ 2015]. Cox-regression model was used for univariate analysis. Harrell's concordance (C) statistic was calculated to measure the incremental accuracy of multivariable models sequentially adjusted for new predictors of thrombotic risk. A P <0.05 was considered statistically significant. Results. At diagnosis, 65 pts (17%) experienced major thrombotic events which included 35 (9%) arterial and 31 (8%) venous thromboses. With a median follow-up of 6.9 y (range 0.08-32.6), 56 (15%) pts developed an arterial or venous thrombotic event, with a total incidence rate of 1.99% pts/year (pt-y); 30 (8%) were arterial and 28 (7%) venous events with incidence rate of 1.00% pt-y and 0.95% pt-y, respectively. Splanchnic vein thrombosis (SVT) represented the most frequent venous events before/at diagnosis (26%). During the follow-up, 16% and 8% of pts experienced myelofibrotic or leukemic progression, and 105 (27%) died, with incidence rate of 2.05% pt-y, 0.95% pt-y and 3.41% pt-y, respectively. In univariate analysis, factors significant for arterial thrombosis after diagnosis were age >65y (HR 2.88; P=0.005), WBC>10x109/L (HR 2.43; P=0.026), presence of >1 generic CV risk factor (HR 2.16; P=0.047), JAK2V617F (HR 3.35; P=0.027) and HMR status (HR 13.1; P=0.027). Conversely, only history of previous thrombosis (HR 3.06; P=0.005) and previous venous event (HR 5.53; P<0.0001) retained significance for predicting venous thrombosis. Pts were effectively stratified according to IPSET and conventional risk model. The risk of thrombosis in IPSET low-, intermediate-, and high-risk categories was 0.67%, 2.05% and 2.95% pt-y, and 1.47% pt-y and 2.71% pt-y in 2-tiered thrombotic risk model. (Figure 1); in revised-IPSET, 0.54%, 2.23%, 2.44% and 2.69 %pt-y in the very low, low, intermediate- and high-risk category. When WBC>10x109/L or HMR variables were incorporated into IPSET model, the C-statistic increased significantly for the prediction of arterial events: from baseline value of 0.68 to 0.74 adding WBC and 0.91 HMR status. The proportion of pts who experienced major bleeding was 3% prior/at diagnosis,and 7% during follow-up, with total incidence rate of 0.94% pt-y. In univariate analysis, predictors for major bleeding during follow-up were age >75y (HR 3.34; P=0.011), WBC>13x109/L (HR 2.33; P=0.035), presence of >1 generic CV risk factor (HR 2.41; P=0.035), particularly hypertension (HR 2.63; P=0.016) and grade-1 fibrosis (HR 2.28; P=0.05). High platelet count and treatment, including antiplatelet and anticoagulant drugs, did not reach statistical significance. Conclusions. Overall, this study identified independent risk factors for major thrombosis and bleeding in pre-PMF. Of interest, we report that HMR status predicted for arterial thrombosis during the follow-up. Pre-PMF pts showed remarkably high rate of venous thrombosis, mostly represented by SVT. The 3-tiered IPSET prognostic model for thrombosis reliably predicted occurrence of thrombotic events in pre-PMF and should be considered as standard reference. Figure 1 Disclosures Rumi: novartis: Honoraria, Research Funding. Thiele:Shire: Research Funding; Incyte: Consultancy, Honoraria, Other: Remuneration, Research Funding; Sanofi: Consultancy, Honoraria, Other: Remuneration; Novartis: Consultancy, Honoraria, Other: Remuneration, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Research Funding. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Incidence and Risk Factors for Central Nervous System Relapse in Very Elderly Patients over 80 with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Two Lysa Studies

Blood ◽

10.1182/blood.v128.22.927.927 ◽

2016 ◽

Vol 128 (22) ◽

pp. 927-927

Author(s):

Aurelie Cabannes-Hamy ◽

Frederic Peyrade ◽

Fabrice Jardin ◽

Jean-Francois Emile ◽

Sylvie Castaigne ◽

...

Keyword(s):

Risk Factors ◽

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

B Cell Lymphoma ◽

Very Elderly ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Cns Relapse

Abstract Background. The prevalence of diffuse large B-cell lymphoma (DLBCL) in patients aged over 80 years is reported to have tripled compared to patients in their sixties. Treating very elderly patients is particularly challenging given the likelihood of comorbidities and concerns over risks of toxicity. One of the most devastating and rapidly fatal complications in DLBCL is central nervous system (CNS) relapse. Most studies reporting incidence and risk factors of CNS relapse concern DLBCL patients under the age of 80 years, and little is known about CNS recurrence in the very elderly, aged over 80 years. CNS prophylaxis is rarely implemented in this population due to the burden of comorbidities, frequent antiplatelet or anticoagulant treatment along with renal failure and hypoalbuminemia, as well as potential prophylaxis toxicity of IV high dose methotrexate and/or the invasiveness of IT therapy. Aim. We retrospectively evaluated the incidence of CNS relapse, risk factors and specific survival in very elderly DLBCL patients aged 80 years Patients and Methods. Data were collected retrospectively from two multicentre, open-label, single arm phase II LYSA trials (LNH 03-7B (NCT01087424) between 2004 and 2007, LNH09-7B (NCT01195714) between 2009 and 2013) evaluating the addition of rituximab or ofatumumab to miniCHOP as front-line therapy. Results. A total of 270 elderly patients were included in the two trials, 150 treated with R-miniCHOP and 120 with O-miniCHOP. Median age was 83 years (range 79-95) and none received CNS prophylaxis. At inclusion, most patients (76%) presented with disseminated disease (Ann Arbor stage III or IV), and 37% had at least two extra-nodal sites. Overall 18% of patients had bone marrow involvement, while renal, adrenal, testis or cavum involvement was rare (4%, 2%, 3%, and 2%, respectively). After a median follow-up of 28.7 months (range 0.1-72.1), 8 (3%) cases of CNS relapse were reported. Median time between inclusion and CNS relapse was 19.2 months (range 3.2 - 32.6). Cumulative 1 and 2-year incidence of CNS relapse was 1.4% (95% CI 3.2-25.4) and 2.5% (95% CI 6.9-9.2), respectively. At inclusion, clinical characteristics of the CNS relapse patients were not significantly different from patients without relapse. At CNS relapse, all patients except one present a performance status ECOG > 2. neurological symptoms were either mild with loss of autonomy, asthenia, hearing impairment, urinary incontinence, or more prominent with delirium, aphasia, intracranial hypertension, or consciousness disorder. Treatment of CNS relapse was a supportive care based- treatment with corticosteroid only in 5 patients, radiation therapy in one patient, and chemotherapy for 2 patients including rituximab-temodal (5 cycles) in one patient and rituximab -aracytine-vepeside (2 cycles) for the other one. Patients survived for a median of 1.5 months after CNS relapse diagnosis (range, 0.4 to 4). The CNS international prognostic index (CNS-IPI) classified 33 (12%) patients in the low-risk group, 164 (62%) in the intermediate-risk group, and 71 (26%) in the high-risk group. The low-risk and intermediate-risk CNS-IPI groups showed 2-year rate of CNS disease of 3%, and the high-risk of 2.8% (p=0.9483). Conclusion. Incidence of CNS relapse in very elderly previously untreated patients is approximately 3% and is associated with a very poor survival. The absence of prophylaxis in this population did not appear to have a strong impact on CNS relapse incidence. Higher number of patients is warranted to identify risk factors for CNS relapse in this population Disclosures Coiffier: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Thieblemont:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Comparison of Prognostic Indices in Diffuse Large B-Cell Lymphoma within the UK NCRI R-CHOP 14 Versus 21 Phase III Trial

Blood ◽

10.1182/blood-2018-99-111824 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2956-2956 ◽

Cited By ~ 1

Author(s):

Mary Gleeson ◽

Nicholas Counsell ◽

David Cunningham ◽

Eliza Hawkes ◽

Anthony Lawrie ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Board ◽

Model Fit ◽

Advisory Committees ◽

Prognostic Groups ◽

Prognostic Indices ◽

The Uk

Abstract Background: The International Prognostic Index (IPI) was first described in 1993 and is the most widely used prognostication tool in diffuse large B-cell lymphoma (DLBCL). Five independent risk factors for OS: age (≤60 yrs versus >60 yrs), stage (I/II versus III/IV), number of extranodal (EN) sites (≤1 versus >1), performance status (PS) (0-1 versus ≥2) and serum lactate dehydrogenase (LDH) (normal versus elevated) were used to design a prognostic model which stratified patients into 4 prognostic groups according to the number of risk factors present: low (0-1), low-intermediate (2), high-intermediate (3), and high-risk (4-5); predicting 5-yr OS rates of 73%, 51%, 43% and 26% and 5-yr relapse-free survival (RFS) rates of 70%, 50%, 49%, 40% respectively. For patients aged ≤60 yrs 3 risk factors (stage, PS and LDH level) remained independently significant for OS, and an age-adjusted (aa) model (the aa-IPI) was proposed which predicted 5-yr OS for the low (0), low-intermediate (1), high-intermediate (2) or high-risk (3) groups of 83%, 69%, 46% and 32% respectively (Shipp et al, 1993). The British Columbia Cancer Agency re-evaluated the role of IPI in the rituximab era in their registry-based cohort of 365 patients in 2007. Although the IPI remained predictive, only 2 (rather than 4) prognostic groups were identified and the authors recommended use of the Revised-IPI (R-IPI) where redistribution of the absolute number of IPI risk factors better stratified patients into 3 prognostic groups: very good (0) good (1,2) and poor (3-5) (Savage et al, 2007). However, a subsequent analysis of pooled data from 3 prospective trials (Ziepert et al, 2010) confirmed that the IPI remained highly predictive of outcomes in the rituximab era. Here we report an evaluation of prognostic indices within the UK NCRI R-CHOP 14 vs 21 prospective trial cohort (Cunningham et al, 2013). Methods: The IPI and R-IPI were applied to the R-CHOP 14 versus 21 trial cohort (n=1,080) and for the subgroup of patients aged ≤60 yrs (n=515) and correlated with OS and progression-free survival (PFS). For patients aged ≤60 yrs the aa-IPI was applied in addition. It was not possible to evaluate the NCCN-IPI in our cohort as absolute LDH values were not collected at enrolment. The association between baseline clinical factors (age, gender, PS, stage, presence of >1 EN site of disease, presence of an elevated LDH, disease bulk and B symptoms) and patient outcomes were investigated in univariable and multivariable analysis (MVA). Performance of the prognostic indices was compared using the Concordance Probability Estimate (CPE) and Akaike's Information Criterion (AIC): CPE evaluates discriminatory power to assess the strength of statistical models (higher values indicate better discrimination); AIC estimates the quality of statistical models relative to each other in terms of fitting the data (lower values indicate a better model fit). Results: After a median follow-up of 6.5 years, both the IPI and R-IPI were significantly associated with OS (Figure 1) and PFS; the IPI performed better than the R-IPI for OS and PFS in terms of discrimination and model fit (Table 1). All IPI factors were significantly associated with OS, and remained in MVA with the exception of disease stage. For patients aged ≤60 yrs, the IPI, R-IPI and aa-IPI were all strongly associated with OS and PFS; the IPI performed best overall of the 3 prognostic indices in terms of discrimination and model fit (Table 2). All individual IPI risk factors, excepting stage, were again found to be significantly associated with OS in MVA for patients aged ≤60 yrs. Conclusion: For the entire DLBCL cohort both the IPI and R-IPI identified meaningful prognostic groups for OS and PFS. Although the IPI outperformed the R-IPI, neither index identified a patient subgroup with an OS of <50% at 5 years. When the analysis was limited to patients aged ≤60 yrs all 3 indices were prognostic, however the IPI performed best overall and was the only risk model to detect a patient subgroup with a 5-yr OS of 45.8%. Our findings suggest that neither the R-IPI nor aa-IPI offer an improvement over the standard IPI in predicting outcomes in DLBCL. Furthermore, our analysis highlights the lack of precision of the traditional prognostic indices in identifying very poor risk patients treated in the rituximab era. Disclosures Cunningham: Roche pharmaceuticals: Research Funding. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Merck KGA: Research Funding; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Celgene: Other: Advisory board, Research Funding; Takeda: Other: Speaker fee; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Pocock:Kent & Canterbury Hospital: Employment. Ardeshna:Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Radford:Celgene: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; BMS: Consultancy, Speakers Bureau; Pfizer: Research Funding. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Johnson:Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Boeringher Ingelheim: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Novartis: Honoraria; Celgene: Honoraria; Eisai: Research Funding; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy.

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Combination of Nilotinib and Pegylated Interferon Alfa-2b Results in High Molecular Response Rates in Chronic Phase CML: Interim Results of the ALLG CML 11 Pinnacle Study

Blood ◽

10.1182/blood-2018-99-110569 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 459-459 ◽

Cited By ~ 4

Author(s):

David T Yeung ◽

Andrew P. Grigg ◽

Naranie Shanmuganathan ◽

Ilona Cunningham ◽

Jake Shortt ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Dose Intensity ◽

Pegylated Interferon ◽

Molecular Response ◽

Lower Quartile ◽

Advisory Committees ◽

Grade Iii

Abstract Alfa Interferon, commonly used in chronic phase chronic myeloid leukemia (CML-CP) in the pre-imatinib era, was able to induce a cytogenetic response in a minority of patients (pts). Pegylated interferon (Peg-IFN) is better tolerated than IFN, and increases molecular response rates when used in combination with imatinib (IM) compared with IM monotherapy (Preudhomme NEJM 2010). The phase II Pinnacle (ALLG CML 11) study evaluated the tolerability and molecular response rate of nilotinib (NIL) with Peg-IFN alfa-2B (PegIntron, MSD) in de novo CML-CP. Pts were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, left ventricular ejection fraction, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Those with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Eligible pts received NIL 300mg BID alone for the first 3 months (mths). PegIntron was then added at 30mcg/week in pts without persistent hematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when pts reverted to TKI monotherapy. Switching to IM 400-600mg QD was allowed for pts with persistent grade II or any grade III/IV toxicity from NIL.. Sixty pts were enrolled from 12 Australian centres. Median age was 48.5 years (range 19-72); 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up (FU) was 28 mths (16-51). Data is presented on an intention to treat basis. Figure 1a shows BCR-ABL1 transcript levels over time. The co-primary end points are MMR (BCR-ABL1 ≤0.1% IS) AT 12 mths and MR4.5 (BCR-ABL1 ≤0.0032% IS) at 24 mths. At 12 mths, MMR and MR4.5 rates were 76.7% (95% CI 63.4-87%). and 43.4% (95% CI 30.1-57.3%), respectively. In 40 evaluable pts at 24 mths, MR4.5 was 50% (95% CI 29.9-70.1%). The median time to MMR and MR4.5 was 5.8 mths and 18 mths respectively for pts achieving these responses (Figs 1B & C). Six pts (10%) had BCR-ABL1 ≥10% at 3 mths - 2 of whom had multiple dose interruptions due to toxicity; 3/6 have since achieved MMR, 1 has BCR-ABL <1%, 2 withdrew of which 1 transformed to AP off study. No BCR-ABL mutation was reported on study. Dose intensities of NIL were assessed in 3 mth blocks. Median and lower quartile NIL dose intensity was 600mg/d for all 3 mth blocks up to mth 24, except for the lower quartile NIL dose of 567mg for the first 3 mths. Eight pts (13%) did not commence Pegintron (2 due to persistent haem toxicities, 4 from GI disturbance, liver/pancreatic enzyme derangements, and 2 from pt preference). Considering Pegintron as a product of protocol assigned dose and duration, adjusted for time from study entry, 22 pts (37%) received >90% of their assigned dose, 13 (22%) received between 50-90% and 25 pts (41%) received <50% of assigned Peg-IFN (Fig 1D). The median duration of Pegintron exposure was 15 mths. Grade III/IV adverse events (AE) attributed to NIL were increased lipase and neutropenia (each 12%), pancreatitis (6%), thrombocytopenia and rash (each 5%). Three thrombotic events occurred: ischemic colitis in a patient on IM monotherapy, femoral artery thrombosis in a 56yo man after 2.5 yrs of NIL, and coronary disease in a 51yo man after 4 yrs of NIL. Grade III/IV AEs attributed to Pegintron were neutropenia (10%), and myalgia, depression and rash (4% each); other common AEs included fatigue (35%), myalgia (23%), flu-like symptoms (21%) and depression (17%). Ten pts (13%) have withdrawn from study: 2 withdrew consent, 5 due to toxicity (pancreatitis, GI upset, rash, high amylase and fatigue), and 3 for failing to consistently achieve BCR-ABL <10% beyond 6 mths. No death occured on study. Three pts lost MMR - 2 were transient; the other was associated with non-compliance. Current TKI treatment for pts on study: 41 on NIL (68%), 9 on IM (15%). Of the 40 pts with 24 mth FU, 15 (38%) received >90% of assigned NIL/IM and Pegintron doses. This interim analysis suggests that combination therapy with NIL and Peg-IFN leads to favourable rates of molecular responses when compared with with NIL monotherapy (Table 1). While the majority of patients did not durably tolerate full dose Pegintron, there was minimal interference with TKI dose intensity. Longer term results, and impact upon treatment free remission outcome of this combination is awaited. Disclosures Yeung: Pfizer: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Specialised Therapeutics Australia: Honoraria; Amgen: Honoraria. Grigg:Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Shanmuganathan:Janssen: Honoraria; Royal Adelaide Hospital Research Fund: Other: Scholarship; Novartis: Honoraria, Other: Travel sponsorship; Bristol-Myers Squibb: Honoraria, Other: Travel sponsorship. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Yong:Celgene: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Research Funding. Branford:Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽

10.1182/blood-2020-139253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 51-52

Author(s):

Sung-Eun Lee ◽

Joon Seong Park ◽

Young Rok Do ◽

Sung-Hyun Kim ◽

Dae Young Zang ◽

...

Keyword(s):

Prospective Study ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitor ◽

Molecular Response ◽

Close Monitoring ◽

Advisory Committees ◽

Deep Molecular Response ◽

Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

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Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Blood ◽

10.1182/blood.v124.21.3339.3339 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3339-3339 ◽

Cited By ~ 4

Author(s):

Ciara Louise Freeman ◽

Mark Dixon ◽

Richard Houghton ◽

Kathryn Humphrey ◽

Gunter Fingerle-Rowson ◽

...

Keyword(s):

Risk Factors ◽

Monoclonal Antibodies ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Signs And Symptoms ◽

Leukemic Cells ◽

Tumour Burden ◽

Advisory Committees ◽

Anti Cd20

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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BAX-Mutated Clonal Hematopoiesis in Patients on Long-Term Venetoclax for Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-137775 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Piers Blombery ◽

Ella R Thompson ◽

Xiangting Chen ◽

Tamia Nguyen ◽

Mary Ann Anderson ◽

...

Keyword(s):

Advisory Committee ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Clonal Hematopoiesis ◽

Eliza Hall Institute ◽

Hall Institute ◽

Over Time

Venetoclax (Ven) is an effective element of treatments for chronic lymphocytic leukemia (CLL) with high response rates observed in the upfront and relapsed/refractory (R/R) settings. In addition to inducing apoptosis in CLL cells, Ven also induces apoptosis within normal and malignant myeloid lineage populations (accounting for its efficacy in the treatment of acute myeloid leukemia). We investigated the effects of Ven outside the target tumor compartment in patients (pts) with CLL receiving long-term continuous Ven and make the novel observation of the development of BAX-mutated clonal hematopoiesis in this heavily pre-treated patient group. 92 pts with CLL receiving continuous non time-limited Ven have been treated at our institutions on clinical trials. Of these, 41 had sufficient (>6 mo) follow up (median 70; range 14-95 mo) and suitable samples available for further analysis. 38/41 (93%) pts had received previous treatment with alkylators and/or fludarabine. In order to assess the non-CLL compartment in these 41 pts we identified those with peripheral blood or bone marrow aspirate samples taken during deep response to Ven demonstrating either minimal (<5%) or no CLL involvement by flow cytometry (sensitivity 10-4). We initially performed unique molecular index (UMI)-based targeted next generation sequencing of apoptosis pathway genes as well a panel of 60 genes recurrently mutated in lymphoid and myeloid malignancy. From these 41 pts we identified mutations in the apoptosis effector BAX in samples from 12 (29%). 20 different BAX mutations were observed across these 12 pts at variant allele frequencies (VAF) consistent with their occurrence in the non-CLL compartment. Mutations included frameshift, nonsense, canonical splice site and missense mutations occurring in key structural elements of BAX consistent with a loss-of-function mechanism (Fig 1A). Interestingly, an enrichment of missense and truncating mutations predicted to escape nonsense mediated decay were observed at the C-terminus of the BAX protein affecting the critical α9 helix. Mutations in this region have previously been shown in cell lines to cause aberrant intracellular BAX localization and abrogation of normal BAX function in apoptosis (Fresquet Blood 2014; Kuwana J Biol Chem 2020). For comparison, NGS targeted sequencing for BAX mutations was performed on samples from cohorts of pts with (i) myeloid or lymphoid malignancy (n=80) or (ii) R/R CLL treated with BTK inhibitors (n=15) after a similar extent of preceding chemotherapy. Neither of these cohorts had previous exposure to Ven. BAX mutations were not detected in any samples from these pts. Longitudinal sampling from pts on Ven harboring BAX mutations in the non-CLL compartment was performed to further understand compartment dynamics over time (in 9 pts over 21-93 months of follow up). Multiple pts demonstrated a progressive increase in VAF of single BAX mutations over time to become clonally dominant within the non-CLL compartment and with observed VAFs consistent with their presence in the myeloid compartment. Mutations in other genes implicated in clonal hematopoiesis and myeloid malignancy including ASXL1, DNMT3A, TET2, U2AF1 and ZRSR2 were also detected in these pts samples. Targeted amplicon single cell sequencing (Mission Bio) demonstrated the co-occurrence of clonally progressive BAX mutations within the same clones as mutations in DNMT3A and ASXL1 as well as the existence of further BAX mutations at low VAF outside these dominant clones which remained non-progressive over time (Fig 1B). In addition, fluctuations in the presence and VAF of myeloid-disease associated mutations was noted with Ven exposure. In aggregate these data are consistent with the existence of a selective pressure within the myeloid compartment of these pts and an interplay of BAX with other mutations in determining survival and enrichment of these clones over time with ongoing Ven therapy. In summary, we have observed the development of BAX-mutated clonal hematopoiesis specifically in pts with CLL treated with long-term Ven. These data are consistent with a multi-lineage pharmacological effect of Ven leading to a survival advantage for clones harboring BAX mutations within the myeloid compartment during chronic Ven exposure. Finally, our data support the further investigation of BAX mutations as a potential resistance mechanism in myeloid malignancies treated with Ven. Disclosures Blombery: Invivoscribe: Honoraria; Amgen: Consultancy; Janssen: Honoraria; Novartis: Consultancy. Anderson:Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Seymour:Celgene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Mei Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Nurix: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria. Huang:Servier: Research Funding; Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.; Genentech: Research Funding. Wei:Janssen: Honoraria, Other; Walter and Eliza Hall Institute: Patents & Royalties; AMGEN: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties.

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Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽

10.1182/blood-2019-122393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2898-2898

Author(s):

Vania Phuoc ◽

Leidy Isenalumhe ◽

Hayder Saeed ◽

Celeste Bello ◽

Bijal Shah ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment

Blood ◽

10.1182/blood-2020-137489 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Josep-Maria Ribera ◽

Olga García ◽

Pau Montesinos ◽

Pilar Martinez ◽

Jordi Esteve ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Allogeneic Hsct ◽

Central Artery

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was <2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

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